Jatrophane Diterpenoids as Modulators of P‑Glycoprotein-Dependent Multidrug Resistance (MDR): Advances of Structure–Activity Relationships and Discovery of Promising MDR Reversal Agents

The phytochemical study of <i>Pedilanthus tithymaloides</i> led to the isolation of 13 jatrophane diterpenoids (<b>1</b>–<b>13</b>), of which eight (<b>1</b>–<b>8</b>) are new. Subsequent structural modification of the major components by esterification, hydrolysis, hydrogenation, or epoxidation yielded 22 new derivatives (<b>14</b>–<b>35</b>). Thus, a jatrophane library containing two series of compounds was established to screen for P-glycoprotein (Pgp)-dependent MDR modulators. The activity was evaluated through a combination of Rho123 efflux and chemoreversal assays on adriamycin resistant human hepatocellular carcinoma cell line HepG2 (HepG2/ADR) and adriamycin resistant human breast adenocarcinoma cell line MCF-7 (MCF-7/ADR). Compounds <b>19</b>, <b>25</b>, and <b>26</b> were identified as potent MDR modulators with greater chemoreversal ability and less cytotoxicity than the third-generation drug tariquidar. The structure–activity relationship (SAR) was discussed, which showed that modifications beyond just increasing the lipophilicity of this class of Pgp inhibitors are beneficial to the activity. Compound <b>26</b>, which exhibited a remarkable metabolic stability in vitro and a favorable antitumor effect in vivo, would serve as a promising lead for the development of new MDR reversal agents

Jatrophane Diterpenoids as Modulators of P‑Glycoprotein-Dependent Multidrug Resistance (MDR): Advances of Structure–Activity Relationships and Discovery of Promising MDR Reversal Agents

The phytochemical study of <i>Pedilanthus tithymaloides</i> led to the isolation of 13 jatrophane diterpenoids (<b>1</b>–<b>13</b>), of which eight (<b>1</b>–<b>8</b>) are new. Subsequent structural modification of the major components by esterification, hydrolysis, hydrogenation, or epoxidation yielded 22 new derivatives (<b>14</b>–<b>35</b>). Thus, a jatrophane library containing two series of compounds was established to screen for P-glycoprotein (Pgp)-dependent MDR modulators. The activity was evaluated through a combination of Rho123 efflux and chemoreversal assays on adriamycin resistant human hepatocellular carcinoma cell line HepG2 (HepG2/ADR) and adriamycin resistant human breast adenocarcinoma cell line MCF-7 (MCF-7/ADR). Compounds <b>19</b>, <b>25</b>, and <b>26</b> were identified as potent MDR modulators with greater chemoreversal ability and less cytotoxicity than the third-generation drug tariquidar. The structure–activity relationship (SAR) was discussed, which showed that modifications beyond just increasing the lipophilicity of this class of Pgp inhibitors are beneficial to the activity. Compound <b>26</b>, which exhibited a remarkable metabolic stability in vitro and a favorable antitumor effect in vivo, would serve as a promising lead for the development of new MDR reversal agents

Mitochondria-Targeted Approach: Remarkably Enhanced Cellular Bioactivities of TPP2a as Selective Inhibitor and Probe toward TrxR

A mitochondria-targeted approach was developed to increase the cellular bioactivities of thioredoxin reductase (TrxR) inhibitors. By being conjugated with a triphenylphosphine (TPP) motif to a previously found TrxR inhibitor 2a, the resulted compound TPP2a can target subcellular mitochondria and efficiently inhibit cellular TrxR, leading to remarkably increased cellular ROS level and mitochondrial apoptosis of HeLa cancer cells. The cellular bioactivities of TPP2a, including its cytotoxicity against a panel of cancer cell lines, dramatically elevated compared with its parental compound 2a. The selectively and covalently interaction of TPP2a with subcellular mitochondrial TrxR was validated by fluorescent microscopy. Moreover, a nonspecific signal quenching coupled strategy was proposed based on the environmentally sensitive fluorescence of TPP2a, which makes it possible to label TrxR by removing the nonspecific backgrounds caused by TPP2a under complex biosettings such as cellular lysates and living cells, implicating a potential of TPP2a for TrxR-specific labeling

Synthesis and Evaluation of Diphenyl Conjugated Imidazole Derivatives as Potential Glutaminyl Cyclase Inhibitors for Treatment of Alzheimer’s Disease

High expression of glutaminyl cyclase (QC) contributes to the initiation of Alzheimer’s disease (AD) by catalyzing the generation of neurotoxic pyroglutamate (pE)-modified β-amyloid (Aβ) peptides. Preventing the generation of pE-Aβs by QC inhibition has been suggested as a novel approach to a disease-modifying therapy for AD. In this work, a series of diphenyl conjugated imidazole derivatives (DPCIs) was rationally designed and synthesized. Analogues with this scaffold exhibited potent inhibitory activity against human QC (hQC) and good <i>in vitro</i> blood–brain barrier (BBB) permeability. Further assessments corroborated that the selected hQC inhibitor <b>28</b> inhibits the activity of hQC, dramatically reduces the generation of pE-Aβs in cultured cells and <i>in vivo</i>, and improves the behavior of AD mice

Synthesis and Identification of New Flavonoids Targeting Liver X Receptor β Involved Pathway as Potential Facilitators of Aβ Clearance with Reduced Lipid Accumulation

Alzheimer’s disease (AD) is associated with impaired Aβ degradation in the brain. Enhancing the process of Aβ clearance is an attractive potential AD therapy. Treatment with LXR agonists may reduce Aβ levels in vivo. However, the clinical potential of many LXR agonists is limited because of their nonselective actions on LXRα/β, which lead to undesired hepatic lipogenesis via LXRα-dependent pathways. In this study, ABCA1 up-regulators were identified from a series of flavonoids and were found to preferentially activate LXRβ and up-regulate expression of ABCA1 and apoE in different cell lines. Further investigations confirmed that these compounds facilitate intracellular Aβ clearance in Aβ-loaded BV2 cells. Administration of compound <b>19</b> reduced total brain Aβ and plaque burden in APP/PS1 double transgenic mice, associated with elevated ABCA1 and apoE expression. Compared with the nonselective LXR agonists, the active compounds reported here induced less accumulation of undesired lipids and triglycerides in HepG2 cells